Natural killer (NK) cells and macrophages (M0) may inhibit formation of metastases. NK cells can function during the bloodborne phase of metastasis, in both normal or biological response modifier (BRM)-treated mice. We have found that hihgly lytic NK cells can also be induced in the tissue of both the lungs and liver by the pyran co-polymer, MVE-2, and that these cells are efficient in inhibiting the formation of metastases in lung and liver. This was demonstrated by preferentially depleting blood and spleen NK activity, which is important for the intravascular inhibition of metastasis, through the use of defined doses of the NK-specific anti-asialo GM1 (asGM1) serum. In this model, MVE-2-augmented NK activity in blood and spleen is deleted, while NK activity in the lungs and liver, along with anti-metastatic effects are retained. High doses of anti-asGM1 ablate lung and liver NK activity, as well as anti-metastatic defenses, indicating that tissue NK activity can play an important role in BRM-induced anti-metastatic responses. Further, we have characterized the cells mediating this tissue resistance to metastasis as large granular lymphocytes (LGL), the cells previously associated with NK activity in rats and humans. We are studing the regulation of these antimetastatic defenses by naturally produced BRMs, and have found that hunan recombinant IL 2 (hrIL2) augments NK activity in the liver and peritoneal cavity, as well as of spleen cells in vitro. Further, low doses of hrIL 2 and mouse recombinant Gamma IFN (mr Gamma IFN) have an additive effect in boosting NK activity in vivo. We are now studying the anti-tumor therapeutic potential of these lymphokines in several experimental models. BRMs also activate M0 for tumoricidal activity. Therefore, doses of anti-asGM1 which ablate all detectable NK activity, but will be used to test the ability of activated M0 to inhibit metastases, in the absence of NK cells.